Dabigatran etexilate, a prodrug of dabigatran, is a novel synthetic direct thrombin inhibitor developed by Germany Boehringer Ingelheim, and belongs to non-peptide thrombin inhibitor. Its dosage form, dabigatran etexilate capsule, was approved for marketing in Europe in March 2008 and became the first new type of oral anticoagulants approved for marketing in the past 50 years after warfarin. Its structural formula is:

There are many reports on the preparation of dabigatran etexilate. At present, the most focused and used method in the industry is to use 3-({2-[(4-Carbamimidoyl-phenylamino)-methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-propionic acid ethyl ester hydrochloride (abbreviation: Amine salts) and n-hexyl chloroformate as starting materials, and acylate to dabigatran etexilate with the alkaline reagent in organic solvents.
During the preparation or storage, some hydrolysis impurity (see patent CN104356111), methyl ester impurity (ethyl ester converted to methyl ester), alcoholysis impurity (see patent CN102964307) and the like are easily generated in dabigatran etexilate. The structures of specific impurity are as follows:

These impurities have quite different chemical properties, so it is very difficult to remove them in one single method. The acetone/water reaction system is selected for the preparation of dabigatran etexilate. The solubility of the alcoholysis impurity in acetone/water system is poor. High purity dabigartran etexilate could not be obtained without effective purification steps.
The patent CN101189224B described a purification method of dabigatran etexilate, comprising: dissolving dabigatran etexilate in ethyl acetate at reflux temperature, cooling the system to 30-35° C. followed by 15-20° C. with stirring, and filtering to get a precipitate; or dissolving dabigatran etexilate in a mixture of acetone/water (80:20), cooling the system to 30° C. and filtering; cooling a filtrate to −9° C., then adding a mixture of acetone/water (80:20) of −9° C. into the filtrate with stirring; filtering to get a precipitate, washing the precipitate with the mixture of acetone/water (80:20) of −9° C. and drying to obtain dabigatran etexilate. This purification method must be repeated for many times, so that the methyl ester impurity can be reduced to a lower level, but the alcoholysis impurity is not substantially removed.
The purification method of dabigatran etexilate was also disclosed in WO2012077136. The disclosed process involves acetone was added to crude product of dabigatran etexilate and stirred to get a clear solution; water was added to the obtained solution to precipitate, filtered, washed the precipitate with water and methyl tert-butyl ether respectively, and then obtained crude product 2 of dabigatran etexilate; a mixture of crude product 2 of dabigatran etexilate and ethyl acetate was heated to reflux temperature with stirring, filtered the reaction mixture through the hyflow bed, washed the bed twice with hot ethyl acetate; ethanol was added to in the filtrate. The reaction mixture was further heated to reflux temperature and stirred, cooled the reaction mixture to 25-35° C., stirred, filtered the solid, washed with ethyl acetate and dried to get pure dabigatran etexilate with a purity of 99.58%. This method uses methyl tert-butyl ether and hot ethyl acetate washing, which has high safety risk in workshop production, and the purity of the product cannot reach the level of the invention.
Another purification method of dabigatran etexilate was disclosed in example 11 of WO2014041559. In this method, crude product of dabigatran etexilate was purified by stirring with a mixture of acetone/with water (8:8 vol), followed by recrystallization from ethyl acetate and ethanol (7:0.3 vol) to obtain the pure dabigatran etexilate with a purity of 99.7%. In another method that described in example 12, the crude product was purified by recrystallization with a mixture of ethyl acetate and acetone (7.0:3.0 vol) to get dabigatran etexilate, purity 99.7%. The method has less effect on removing alcoholysis impurity than the present invention, and the purity of the product cannot reach the level of the invention.
To sum up, the methods for purifying dabigatran etexilate reported in the literature have the problems of complicated operation, low safety factor and difficulty in substantially removing all kinds of impurities completely. Therefore, it is very necessary to develop a purification method that is easy to operate and can greatly reduce all kinds of impurities existing in dabigatran etexilate. In addition, the preparation of high-purity dabigatran etexilate also provides a basis for the preparation of high-purity dabigatran etexilate mesylate.